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Zarrella S, Miranda MR, Covelli V, Restivo I, Novi S, Pepe G, Tesoriere L, Rodriquez M, Bertamino A, Campiglia P, Tecce MF, Vestuto V. Endoplasmic Reticulum Stress and Its Role in Metabolic Reprogramming of Cancer. Metabolites 2025; 15:221. [PMID: 40278350 PMCID: PMC12029571 DOI: 10.3390/metabo15040221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/14/2025] [Accepted: 03/18/2025] [Indexed: 04/26/2025] Open
Abstract
Background/Objectives: Endoplasmic reticulum (ER) stress occurs when ER homeostasis is disrupted, leading to the accumulation of misfolded or unfolded proteins. This condition activates the unfolded protein response (UPR), which aims to restore balance or trigger cell death if homeostasis cannot be achieved. In cancer, ER stress plays a key role due to the heightened metabolic demands of tumor cells. This review explores how metabolomics can provide insights into ER stress-related metabolic alterations and their implications for cancer therapy. Methods: A comprehensive literature review was conducted to analyze recent findings on ER stress, metabolomics, and cancer metabolism. Studies examining metabolic profiling of cancer cells under ER stress conditions were selected, with a focus on identifying potential biomarkers and therapeutic targets. Results: Metabolomic studies highlight significant shifts in lipid metabolism, protein synthesis, and oxidative stress management in response to ER stress. These metabolic alterations are crucial for tumor adaptation and survival. Additionally, targeting ER stress-related metabolic pathways has shown potential in preclinical models, suggesting new therapeutic strategies. Conclusions: Understanding the metabolic impact of ER stress in cancer provides valuable opportunities for drug development. Metabolomics-based approaches may help identify novel biomarkers and therapeutic targets, enhancing the effectiveness of antitumor therapies.
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Affiliation(s)
- Salvatore Zarrella
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Maria Rosaria Miranda
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
- NBFC, National Biodiversity Future Center, 90133 Palermo, Italy
| | - Verdiana Covelli
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano, 49, 80131 Napoli, Italy; (V.C.); (M.R.)
| | - Ignazio Restivo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Via Archirafi 28, 90123 Palermo, Italy; (I.R.); (L.T.)
| | - Sara Novi
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Giacomo Pepe
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
- NBFC, National Biodiversity Future Center, 90133 Palermo, Italy
| | - Luisa Tesoriere
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Via Archirafi 28, 90123 Palermo, Italy; (I.R.); (L.T.)
| | - Manuela Rodriquez
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano, 49, 80131 Napoli, Italy; (V.C.); (M.R.)
| | - Alessia Bertamino
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Pietro Campiglia
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Mario Felice Tecce
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Vincenzo Vestuto
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
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Wu N, Bayatpour S, Hylemon PB, Aseem SO, Brindley PJ, Zhou H. Gut Microbiome and Bile Acid Interactions: Mechanistic Implications for Cholangiocarcinoma Development, Immune Resistance, and Therapy. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:397-408. [PMID: 39730075 PMCID: PMC11841492 DOI: 10.1016/j.ajpath.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/05/2024] [Accepted: 11/12/2024] [Indexed: 12/29/2024]
Abstract
Cholangiocarcinoma (CCA) is a rare but highly malignant carcinoma of bile duct epithelial cells with a poor prognosis. The major risk factors of CCA carcinogenesis and progression are cholestatic liver diseases. The key feature of primary sclerosing cholangitis and primary biliary cholangitis is chronic cholestasis. It indicates a slowdown of hepatocyte secretion of biliary lipids and metabolites into bile as well as a slowdown of enterohepatic circulation (bile acid recirculation) of bile acids with dysbiosis of the gut microbiome. This leads to enterohepatic recirculation and an increase of toxic secondary bile acids. Alterations of serum and liver bile acid compositions via the disturbed enterohepatic circulation of bile acids and the disturbance of the gut microbiome then activate a series of hepatic and cancer cell signaling pathways that promote CCA carcinogenesis and progression. This review focuses on the mechanistic roles of bile acids and the gut microbiome in the pathogenesis and progression of CCA. It also evaluates the therapeutic potential of targeting the gut microbiome and bile acid-mediated signaling pathways for the therapy and prophylaxis of CCA.
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Affiliation(s)
- Nan Wu
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia
| | - Sareh Bayatpour
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia
| | - Phillip B Hylemon
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia; Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Sayed O Aseem
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, Virginia; Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia
| | - Paul J Brindley
- Department of Microbiology, Immunology and Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond Veterans Affairs Medical Center, Richmond, Virginia; Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, Virginia.
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Fu C, Jin H, Wang Y, Xu H. Clinicopathological features and surgical treatments of intraductal papillary neoplasm of the bile duct: a case report and literature review. Front Med (Lausanne) 2024; 11:1443599. [PMID: 39386752 PMCID: PMC11461345 DOI: 10.3389/fmed.2024.1443599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 09/02/2024] [Indexed: 10/12/2024] Open
Abstract
Intraductal papillary neoplasm of bile duct (IPNB), as a precancerous lesion of cholangiocarcinoma, is a rare biliary tract tumor. A 66-year-old female patient was found to have a bile duct mass by routine examination. The liver function tests and tumor markers were normal. Imaging findings revealed a 2.6 cm mass in the common hepatic duct, accompanied by dilatation of both intrahepatic and extrahepatic bile ducts. The patient underwent open extrahepatic bile duct resection, cholecystectomy and Roux-en-Y hepaticojejunostomy. We also conducted a literature review to summarize the clinicopathological features and surgical treatments of IPNB.
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Affiliation(s)
- Chang Fu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Hengwei Jin
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Yongxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Hongji Xu
- Department of Abdominal Surgery, Guiqian International General Hospital, Guiyang, China
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Sharma R, Majee C, Mazumder R, Mazumder A, Tyagi PK, Chaitanya MVNL. Insight Into the Role of Alkaloids in the Different Signalling Pathways of Cholangiocarcinoma. JOURNAL OF NATURAL REMEDIES 2024:43-58. [DOI: 10.18311/jnr/2024/34661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 09/19/2023] [Indexed: 01/04/2025]
Abstract
Throughout the biliary tree, a variety of cells give rise to cholangiocarcinomas, a broad group of malignancies. The fact that these tumours are silent and asymptomatic, especially in their early stages, seriously impairs the effectiveness of available therapeutic options and contributes to their poor prognosis. Over the past few years, increased efforts have been made to identify the aetiology and signalling pathways of these tumours and to create more potent therapies. Since alkaloids are more potent and effective against cholangiocarcinoma cell lines, they have gained importance in the treatment of cholangiocarcinoma. In cell lines with cholangiocarcinoma, they promote apoptosis. and restrict the spread of cells, departure, and development. This review highlights the recent developments in the study of CCA, primarily concentrating on the regulation of the signalling pathway and revealing alkaloids demonstrating strong anti-cholangiocarcinoma efficacy, providing researchers with a rapid approach for the future development of powerful and efficient pharmaceutical compounds.
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Tan S, Machrumnizar M. Fish and Food-Fatale: Food-borne Trematode Opisthorchis viverrini and Cholangiocarcinoma. Helminthologia 2023; 60:287-299. [PMID: 38222491 PMCID: PMC10787637 DOI: 10.2478/helm-2023-0036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 10/20/2023] [Indexed: 01/16/2024] Open
Abstract
Neglected Tropical Diseases (NTDs) are a group of communicable diseases with a long history with human beings. NTDs are the proxy of poverty since they affect those in low-income and extreme-poverty populations, as those populations lack access to proper health care, clean water, sanitary conditions, and hygiene. NTDs create losses for a nation that come from the health and the economic sectors as well since the costs of diagnosis, prevention, and treatment strain the national purse strings. One of the 20 different forms of NTDs on the list is food-borne trematodes, comprises of Fasciola, Paragonimus, Clonorchis, and Opisthorchis. Currently, it is estimated that food-borne trematodes can cause a devastating effect on mortality and morbidity. All of them are zoonotic, as humans become infected by ingestion of a second intermediate host, such as freshwater snails, fish, or water vegetables. Opisthorchis viverrini, one of the food-borne trematodes that can be found mostly in South East Asia regions, especially in the Mekong basin, is regarded as a group 1 carcinogen leading to cholangiocarcinoma (CCA). This study aims to present the updated review of Opisthorchis viverrini and CCA.
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Affiliation(s)
- S. Tan
- Department of Parasitology, Faculty of Medicine, Universitas Trisakti, Jakarta11440, Indonesia
- Tropical Diseases and Public Health Research Centre, Faculty of Medicine, Universitas Trisakti, Jakarta11440, Indonesia
| | - M. Machrumnizar
- Department of Parasitology, Faculty of Medicine, Universitas Trisakti, Jakarta11440, Indonesia
- Tropical Diseases and Public Health Research Centre, Faculty of Medicine, Universitas Trisakti, Jakarta11440, Indonesia
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Gehl V, O'Rourke CJ, Andersen JB. Immunogenomics of cholangiocarcinoma. Hepatology 2023:01515467-990000000-00649. [PMID: 37972940 DOI: 10.1097/hep.0000000000000688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/16/2023] [Indexed: 11/19/2023]
Abstract
The development of cholangiocarcinoma spans years, if not decades, during which the immune system becomes corrupted and permissive to primary tumor development and metastasis. This involves subversion of local immunity at tumor sites, as well as systemic immunity and the wider host response. While immune dysfunction is a hallmark of all cholangiocarcinoma, the specific steps of the cancer-immunity cycle that are perturbed differ between patients. Heterogeneous immune functionality impacts the evolutionary development, pathobiological behavior, and therapeutic response of these tumors. Integrative genomic analyses of thousands of primary tumors have supported a biological rationale for immune-based stratification of patients, encompassing immune cell composition and functionality. However, discerning immune alterations responsible for promoting tumor initiation, maintenance, and progression from those present as bystander events remains challenging. Functionally uncoupling the tumor-promoting or tumor-suppressing roles of immune profiles will be critical for identifying new immunomodulatory treatment strategies and associated biomarkers for patient stratification. This review will discuss the immunogenomics of cholangiocarcinoma, including the impact of genomic alterations on immune functionality, subversion of the cancer-immunity cycle, as well as clinical implications for existing and novel treatment strategies.
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Affiliation(s)
- Virag Gehl
- Department of Health and Medical Sciences, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
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Oey O, Sunjaya AF, Khan Y, Redfern A. Stromal inflammation, fibrosis and cancer: An old intuition with promising potential. World J Clin Oncol 2023; 14:230-246. [PMID: 37583950 PMCID: PMC10424089 DOI: 10.5306/wjco.v14.i7.230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/07/2023] [Accepted: 06/21/2023] [Indexed: 07/19/2023] Open
Abstract
It is now well established that the biology of cancer is influenced by not only malignant cells but also other components of the tumour microenvironment. Chronic inflammation and fibrosis have long been postulated to be involved in carcinogenesis. Chronic inflammation can promote tumorigenesis via growth factor/cytokine-mediated cellular proliferation, apoptotic resistance, immunosuppression; and free-radical-induced oxidative deoxyribonucleic acid damage. Fibrosis could cause a perturbation in the dynamics of the tumour microenvironment, potentially damaging the genome surveillance machinery of normal epithelial cells. In this review, we will provide an in-depth discussion of various diseases characterised by inflammation and fibrosis that have been associated with an increased risk of malignancy. In particular, we will present a comprehensive overview of the impact of alterations in stromal composition on tumorigenesis, induced as a consequence of inflammation and/or fibrosis. Strategies including the application of various therapeutic agents with stromal manipulation potential and targeted cancer screening for certain inflammatory diseases which can reduce the risk of cancer will also be discussed.
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Affiliation(s)
- Oliver Oey
- Faculty of Medicine, University of Western Australia, Perth 6009, Crawley NA, Australia
- Department of Medical Oncology, Sir Charles Gardner Hospital, Nedlands 6009, Australia
| | - Angela Felicia Sunjaya
- Institute of Cardiovascular Science, University College London, London WC1E 6DD, United Kingdom
| | - Yasir Khan
- Department of Medical Oncology, St John of God Midland Public and Private Hospital, Midland 6056, WA, Australia
| | - Andrew Redfern
- Department of Medical Oncology, Fiona Stanley Hospital, Murdoch 6150, WA, Australia
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Ibrahim MK, Simon TG, Rinella ME. Extrahepatic Outcomes of Nonalcoholic Fatty Liver Disease: Nonhepatocellular Cancers. Clin Liver Dis 2023; 27:251-273. [PMID: 37024206 DOI: 10.1016/j.cld.2023.01.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, including isolated steatosis, steatohepatitis, and cirrhosis. The overall global prevalence of NAFLD is estimated to be 30%, and the associated clinical and economic burden will continue to increase. NAFLD is a multisystemic disease with established links to cardiovascular disease, type 2 diabetes, metabolic syndrome, chronic kidney disease, polycystic ovarian syndrome, and intra- and extrahepatic malignancies. In this article the authors review the potential mechanisms and current evidence for the association between NAFLD and extrahepatic cancers and the resultant impact on clinical outcomes.
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Affiliation(s)
- Maryam K Ibrahim
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Tracey G Simon
- Harvard Medical School, Boston, MA, USA; Division of Gastroenterology and Hepatology, Massachusetts General Hospital, Boston, MA, USA; Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA
| | - Mary E Rinella
- University of Chicago Pritzker School of Medicine; University of Chicago Hospitals.
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Loilome W, Namwat N, Jusakul A, Techasen A, Klanrit P, Phetcharaburanin J, Wangwiwatsin A. The Hallmarks of Liver Fluke Related Cholangiocarcinoma: Insight into Drug Target Possibility. Recent Results Cancer Res 2023; 219:53-90. [PMID: 37660331 DOI: 10.1007/978-3-031-35166-2_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Cholangiocarcinoma (CCA) is a malignant tumor of the biliary tree that is classified into three groups based on its anatomic location: intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA). Perihilar CCA is the most common type and accounts for 50-60% of CCA cases. It is followed by distal CCA and then intrahepatic CCA that account for 20-30% and 10-20% of cases, respectively. This chapter discusses the hallmarks of liver fluke related CCA and explores insights into drug target possibilities.
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Affiliation(s)
- Watcharin Loilome
- Department of System Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
| | - Nisana Namwat
- Department of System Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Apinya Jusakul
- Faculty of Associated Medical Science, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Anchalee Techasen
- Faculty of Associated Medical Science, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Poramate Klanrit
- Department of System Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Jutarop Phetcharaburanin
- Department of System Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Arporn Wangwiwatsin
- Department of System Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
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Yang M, Li M, Lyu Z, Yang Z. Implication of Ferroptosis in Cholangiocarcinoma: A Potential Future Target? Cancer Manag Res 2023; 15:335-342. [PMID: 37063167 PMCID: PMC10093512 DOI: 10.2147/cmar.s406150] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 03/30/2023] [Indexed: 04/18/2023] Open
Abstract
Cholangiocarcinoma (CCA), the second most common liver neoplasm, has a poor overall 5-year survival rate of less than 10%. A deeper understanding of the molecular pathogenesis contributing to CCA progression is essential for developing better therapeutic approaches to manage this disease. Ferroptosis, an oxidative iron-dependent form of regulated cell death, has been reported to be involved in tumorigenesis and progression. In particular, ferroptosis and inflammation, which are common issues in cholangiocarcinogenesis and CCA development, might be in concert with disease progression. Notably, the key feature of cancer cells is "iron addiction", which is crucial for the high metabolic demand in carcinogenesis and cancer progression. Additionally, iron metabolism is of great importance in ferroptosis. Moreover, that cancer cells are vulnerable to ferroptosis might be a possible mechanism of CCA development. Although the underlying mechanism of how ferroptosis is implicated in CCA development requires further investigation, developing a new strategy combined with a pro-ferroptotic treatment would be an exciting CCA treatment approach in the future.
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Affiliation(s)
- Mingyu Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
| | - Meng Li
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
| | - Zhuozhen Lyu
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
| | - Zhen Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
- Correspondence: Zhen Yang, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, JingWu Road, Jinan, Shandong, 25000, People’s Republic of China, Tel +86 15168867123, Email
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Probing photoprotection properties of lipophilic chain conjugated thiourea-aryl group molecules to attenuate ultraviolet-A induced cellular and DNA damages. Sci Rep 2022; 12:20907. [PMID: 36463260 PMCID: PMC9719470 DOI: 10.1038/s41598-022-25515-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 11/30/2022] [Indexed: 12/07/2022] Open
Abstract
Ultraviolet-A (UVA) radiation is a major contributor to reactive oxygen species (ROS), reactive nitrite species (RNS), inflammation, and DNA damage, which causes photoaging and photocarcinogenesis. This study aimed to evaluate the UVA protective potential of lipophilic chain conjugated thiourea-substituted aryl group molecules against UVA-induced cellular damages in human dermal fibroblasts (BJ cell line). We tested a series of nineteen (19) molecules for UVA photoprotection, from which 2',5'-dichlorophenyl-substituted molecule DD-04 showed remarkable UVA protection properties compared to the reference (benzophenone). The results indicate that DD-04 significantly reduced intracellular ROS and nitric oxide (NO) as compared to the UVA-irradiated control (p < 0.001). Moreover, the compound DD-04 showed anti-inflammatory activity as it significantly reduced the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) pro-inflammatory cytokines produced by THP-1 (human monocytic) cells (p < 0.05). DNA damage was also prevented by DD-04 treatment in the presence of UVA. It was observed that DD-04 significantly reduced the number of cyclobutane pyrimidine dimers (CPDs) when compared to the UVA-irradiated control (p < 0.001). Finally, the DNA strand breaks were checked and a single intact DNA band was seen upon treatment with DD-04 in the presence of UVA. In conclusion, DD-04 can be considered a potential candidate UVA filter due to its photoprotective potential.
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Liu T, Wang X, Jia P, Liu C, Wei Y, Song Y, Li S, Liu L, Wang B, Shi H. Association between serum arginine levels and cancer risk: A community-based nested case-control study. Front Nutr 2022; 9:1069113. [PMID: 36466394 PMCID: PMC9712959 DOI: 10.3389/fnut.2022.1069113] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 11/02/2022] [Indexed: 01/10/2024] Open
Abstract
OBJECTIVE The effect of arginine on tumors appears to be bidirectional. The association of serum arginine with the risk of incident cancer remains uncovered at present. We aimed to investigate the prospective relationship of baseline serum arginine concentrations with the risk of incident cancer in hypertensive participants. MATERIALS AND METHODS A nested, case-control study with 1,389 incident cancer cases and 1,389 matched controls was conducted using data from the China H-Type Hypertension Registry Study (CHHRS). Conditional logistic regression analyses were performed to evaluate the association between serum arginine and the risk of the overall, digestive system, non-digestive system, and site-specific cancer. RESULTS Compared with matched controls, cancer patients had higher levels of arginine (21.41 μg/mL vs. 20.88 μg/mL, p < 0.05). When serum arginine concentrations were assessed as quartiles, compared with participants in the lowest arginine quartile, participants in the highest arginine quartile had a 32% (OR = 1.32, 95% CI: 1.03 to 1.71), and 68% (OR = 1.68, 95% CI: 1.09 to 2.59) increased risk of overall and digestive system cancer, respectively, in the adjusted models. In the site-specific analysis, each standard deviation (SD) increment of serum arginine was independently and positively associated with the risk of colorectal cancer (OR = 1.35, 95% CI: 1.01 to 1.82) in the adjusted analysis. CONCLUSION We found that hypertensive individuals with higher serum arginine levels exhibited a higher risk of overall, digestive system, and colorectal cancer.
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Affiliation(s)
- Tong Liu
- Department of Gastrointestinal Surgery/Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China
- Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Xiaomeng Wang
- Department of Education, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Pingping Jia
- Department of Gastrointestinal Surgery/Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China
- Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Chenan Liu
- Department of Gastrointestinal Surgery/Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China
- Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Yaping Wei
- Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, College of Food Sciences and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Yun Song
- Shenzhen Evergreen Medical Institute, Shenzhen, China
| | - Shuqun Li
- Shenzhen Evergreen Medical Institute, Shenzhen, China
| | - Lishun Liu
- Shenzhen Evergreen Medical Institute, Shenzhen, China
| | - Binyan Wang
- Shenzhen Evergreen Medical Institute, Shenzhen, China
| | - Hanping Shi
- Department of Gastrointestinal Surgery/Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China
- Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
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Gu D, Zhang M, Wang Y, Bai Y, Wang X, Deng G. Causal effect of autoimmune liver diseases on cancer: Meta-analyses of cohort studies and Mendelian randomization study. Liver Int 2022; 42:2216-2226. [PMID: 35775855 DOI: 10.1111/liv.15355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/26/2022] [Accepted: 06/29/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Prior studies suggested that patients with autoimmune liver diseases (AiLDs) had an increased risk of cancer, whereas the causal effect remained unclear. METHODS Meta-analyses concerning the relationship between AiLD and cancer risk were performed to calculate the pooled relative risk (RR) and corresponding 95% confidence intervals (CIs). Then, the associations with a p value of <.05 were further validated by two-sample Mendelian randomization studies. RESULTS A total of 37 cohort studies covering more than 34 558 patients were included, and we observed an increased risk of overall cancers (pooled RR = 3.64, 95% CI: 2.64-5.03, p < .001) and cancer-related death (pooled RR = 2.48, 95% CI: 1.73-3.53, p < .001) for patients with AiLD. Besides, overall and several site-specific cancers risk were found in patients with primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC) (p < .05). However, associations between genetically predisposed AIH, PBC, and PSC and the risk of specific cancers did not reach a significant level, except for PBC and gastric cancer (OR = 0.96, 95% CI: 0.93-0.99; p = .02). CONCLUSIONS In addition to hepatobiliary cancer, results from the meta-analyses suggest that patients with AiLD might have an increased risk of several extrahepatobiliary cancers. However, the causal role of AiLD in cancer development needs to be further investigated.
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Affiliation(s)
- Dongqing Gu
- Department of Infectious Diseases, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Min Zhang
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Yutong Wang
- Department of Epidemiology and Biostatistics, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China
| | - Ye Bai
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Xin Wang
- Department of Epidemiology and Biostatistics, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China
| | - Guohong Deng
- Department of Infectious Diseases, First Affiliated Hospital, Army Medical University, Chongqing, China
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14
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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15
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The Breast Cancer Protooncogenes HER2, BRCA1 and BRCA2 and Their Regulation by the iNOS/NOS2 Axis. Antioxidants (Basel) 2022; 11:antiox11061195. [PMID: 35740092 PMCID: PMC9227079 DOI: 10.3390/antiox11061195] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 02/04/2023] Open
Abstract
The expression of inducible nitric oxide synthase (iNOS; NOS2) and derived NO in various cancers was reported to exert pro- and anti-tumorigenic effects depending on the levels of expression and the tumor types. In humans, the breast cancer level of iNOS was reported to be overexpressed, to exhibit pro-tumorigenic activities, and to be of prognostic significance. Likewise, the expression of the oncogenes HER2, BRCA1, and BRCA2 has been associated with malignancy. The interrelationship between the expression of these protooncogenes and oncogenes and the expression of iNOS is not clear. We have hypothesized that there exist cross-talk signaling pathways between the breast cancer protooncogenes, the iNOS axis, and iNOS-mediated NO mutations of these protooncogenes into oncogenes. We review the molecular regulation of the expression of the protooncogenes in breast cancer and their interrelationships with iNOS expression and activities. In addition, we discuss the roles of iNOS, HER2, BRCA1/2, and NO metabolism in the pathophysiology of cancer stem cells. Bioinformatic analyses have been performed and have found suggested molecular alterations responsible for breast cancer aggressiveness. These include the association of BRCA1/2 mutations and HER2 amplifications with the dysregulation of the NOS pathway. We propose that future studies should be undertaken to investigate the regulatory mechanisms underlying the expression of iNOS and various breast cancer oncogenes, with the aim of identifying new therapeutic targets for the treatment of breast cancers that are refractory to current treatments.
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16
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Chulkova SV, Loginov VI, Podluzhnyi DV, Egorova AV, Syskova AY, Semichev DG, Gladilina IA, Kudashkin NE. [The role of molecular genetic factors in the development of cholangiocellular carcinoma]. Arkh Patol 2022; 84:76-83. [PMID: 35639847 DOI: 10.17116/patol20228403176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The article lists the main inducers of cholangiocarcinogenesis. The main inflammatory mediators (IL-6, nitric oxide, COX2) have been considered. Data on the study of gene mutations in cholangiocarcinomas are presented. The spectrum of genetic mutations depends on the biliary cancer origin (FGFR2 with intrahepatic cholangiocarcinoma, PRKACA, PRKACB with extrahepatic cholangiocarcinoma). Mutations in the KRAS, TP53, ARIAD1A genes are common in extrahepatic bile duct cancer. The role of epigenetic changes such as DNA hypermethylation, histone modifications, chromatin remodeling, as well as disturbances in miRNA expression is presented. A number of epigenetic features, such as the presence of a TP53 mutations with hypermethylation of p14ARF, DAPK, and/or ASC, correlate with a more aggressive course of the disease. The role of the SOX17 gene in the development of drug resistance is highlighted. The study of the molecular genetic features of extrahepatic bile duct cancer can help to better understand the pathogenesis of this type of tumor, to establish new prognostic and diagnostic markers of the disease.
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Affiliation(s)
- S V Chulkova
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia.,N.I. Pirogov Russian National Research Medical University, Moscow, Russia
| | - V I Loginov
- Scientific Research Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - D V Podluzhnyi
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - A V Egorova
- N.I. Pirogov Russian National Research Medical University, Moscow, Russia
| | - A Yu Syskova
- N.I. Pirogov Russian National Research Medical University, Moscow, Russia
| | - D G Semichev
- N.I. Pirogov Russian National Research Medical University, Moscow, Russia
| | - I A Gladilina
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia.,N.I. Pirogov Russian National Research Medical University, Moscow, Russia
| | - N E Kudashkin
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia.,N.I. Pirogov Russian National Research Medical University, Moscow, Russia
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17
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Cadamuro M, Strazzabosco M. Inflammatory pathways and cholangiocarcinoma risk mechanisms and prevention. Adv Cancer Res 2022; 156:39-73. [PMID: 35961707 PMCID: PMC10916841 DOI: 10.1016/bs.acr.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Cholangiocarcinoma (CCA), a neoplasm burdened by a poor prognosis and currently lacking adequate therapeutic treatments, can originate at different levels of the biliary tree, in the intrahepatic, hilar, or extrahepatic area. The main risk factors for the development of CCA are the presence of chronic cholangiopathies of various etiology. To date, the most studied prodromal diseases of CCA are primary sclerosing cholangitis, Caroli's disease and fluke infestations, but other conditions, such as metabolic syndrome, nonalcoholic fatty liver disease and obesity, are emerging as associated with an increased risk of CCA development. In this review, we focused on the analysis of the pro-inflammatory mechanisms that induce the development of CCA and on the role of cells of the immune response in cholangiocarcinogenesis. In very recent times, these cellular mechanisms have been the subject of emerging studies aimed at verifying how the modulation of the inflammatory and immunological responses can have a therapeutic significance and how these can be used as therapeutic targets.
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Affiliation(s)
| | - Mario Strazzabosco
- Liver Center, Department of Internal Medicine, Yale University, New Haven, CT, United States.
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18
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Desjonqueres E, Campani C, Marra F, Zucman-Rossi J, Nault JC. Preneoplastic lesions in the liver: Molecular insights and relevance for clinical practice. Liver Int 2022; 42:492-506. [PMID: 34982503 DOI: 10.1111/liv.15152] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the most frequent primary liver cancers, accounting for approximately 80% and 15%, respectively. HCC carcinogenesis occurs mostly in cirrhosis and is a complex multi-step process, from precancerous lesions (low-grade and high-grade dysplastic nodules) to progressed HCC. During the different stages of liver carcinogenesis, there is an accumulation of pathological, genetic and epigenetic changes leading to initiation, malignant transformation and finally tumour progression. In contrast, a small subset of HCC occurs in normal liver from the transformation of hepatocellular adenoma (HCA), a benign hepatocellular tumour. The recent molecular classification enables to stratify HCAs according to their risk of complication, in particular malignant transformation, associated with mutations in exon 3 of the catenin beta 1 (CTNNB1) gene. Cholangiocarcinoma (CCA) derives from the multistep malignant transformation of preneoplastic lesions, like biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB), for which a pre-operative diagnosis remains difficult. Different genetic alterations are involved in BilIN and IPNB progression, leading to the development of tubular or intestinal adenocarcinoma. The aims of this review are to describe the main clinical and molecular features of preneoplastic lesions leading to the development of HCC and CCA, their implications in clinical practice and the perspectives for future research.
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Affiliation(s)
- Elvire Desjonqueres
- Service d'hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France.,Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.,Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France
| | - Claudia Campani
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.,Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France.,Hôpital Européen Georges Pompidou, APHP, Paris, France
| | - Jean-Charles Nault
- Service d'hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France.,Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.,Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France
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19
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Sahebnasagh A, Saghafi F, Negintaji S, Hu T, Shabani-Borujeni M, Safdari M, Ghaleno HR, Miao L, Qi Y, Wang M, Liao P, Sureda A, Simal-Gándara J, Nabavi SM, Xiao J. Nitric Oxide and Immune Responses in Cancer: Searching for New Therapeutic Strategies. Curr Med Chem 2022; 29:1561-1595. [PMID: 34238142 DOI: 10.2174/0929867328666210707194543] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 05/05/2021] [Accepted: 05/15/2021] [Indexed: 02/08/2023]
Abstract
In recent years, there has been an increasing interest in understanding the mysterious functions of nitric oxide (NO) and how this pleiotropic signaling molecule contributes to tumorigenesis. This review attempts to expose and discuss the information available on the immunomodulatory role of NO in cancer and recent approaches to the role of NO donors in the area of immunotherapy. To address the goal, the following databases were searched to identify relevant literature concerning empirical evidence: The Cochrane Library, Pubmed, Medline, and EMBASE from 1980 through March 2020. Valuable attempts have been made to develop distinctive NO-based cancer therapy. Although the data do not allow generalization, the evidence seems to indicate that low/moderate levels may favor tumorigenesis, while higher levels would exert antitumor effects. In this sense, the use of NO donors could have an important therapeutic potential within immunotherapy, although there are still no clinical trials. The emerging understanding of NO-regulated immune responses in cancer may help unravel the recent features of this "doubleedged sword" in cancer physiological and pathologic processes and its potential use as a therapeutic agent for cancer treatment. In short, in this review, we discuss the complex cellular mechanism in which NO, as a pleiotropic signaling molecule, participates in cancer pathophysiology. We also debate the dual role of NO in cancer and tumor progression and clinical approaches for inducible nitric oxide synthase (iNOS) based therapy against cancer.
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Affiliation(s)
- Adeleh Sahebnasagh
- Clinical Research Center, Department of Internal Medicine, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Fatemeh Saghafi
- Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Sina Negintaji
- Student Research Committee, School of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Tingyan Hu
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Mojtaba Shabani-Borujeni
- Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammadreza Safdari
- Department of Orthopedic Surgery, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Hassan Rezai Ghaleno
- Department of Surgery, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Lingchao Miao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao
| | - Yaping Qi
- Purdue Quantum Science and Engineering Institute, Purdue University, West Lafayette, IN 47907, USA
| | - Mingfu Wang
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Pan Liao
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Antoni Sureda
- Research Group on Community Nutrition and Oxidative Stress, and Balearic Islands Health Research Institute (IdISBa), University of the Balearic Islands, Palma de Mallorca, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III, Madrid, Spain
| | - Jesus Simal-Gándara
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E-32004 Ourense, Spain
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Jianbo Xiao
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E-32004 Ourense, Spain
- International Research Centre for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
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20
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Interweaving of Reactive Oxygen Species and Major Neurological and Psychiatric Disorders. ANNALES PHARMACEUTIQUES FRANÇAISES 2021; 80:409-425. [PMID: 34896378 DOI: 10.1016/j.pharma.2021.11.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 10/27/2021] [Accepted: 11/29/2021] [Indexed: 11/21/2022]
Abstract
Reactive oxygen species are found to be having a wide range of biological effects ranging from regulating functions in normal physiology to alteration and damaging various processes and cell components causing a number of diseases. Mitochondria is an important organelle responsible for energy production and in many signalling mechanisms. The electron transport chain in mitochondria where oxidative phosphorylation takes place is also coupled with the generation of reactive oxygen species (ROS). Changes in normal homeostasis and overproduction of reactive oxygen species by various sources are found to be involved in multiple neurological and major neurodegenerative diseases. This review summarises the role of reactive oxygen species and the mechanism of neuronal loss in major neuronal disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Depression, and Schizophrenia.
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21
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Yan H, Chen S, Qiong Y, Cai L. Preoperative prealbumin-to-fibrinogen ratio predict Survival Outcomes in hepatocellular carcinoma patients after hepatic resection. J Med Biochem 2021; 41:290-298. [PMID: 36042905 PMCID: PMC9375540 DOI: 10.5937/jomb0-32980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 10/12/2021] [Indexed: 11/22/2022] Open
Abstract
Background This study aimed to evaluate the clinical application of the preoperative prealbumin-to-fibrinogen ratio (PFR) in the clinical diagnosis of hepatocellular carcinoma (HCC) patients and its prognostic value. Methods The clinical and laboratory data of 269 HCC patients undergoing surgical treatment from January 2012 to January 2017 in Taizhou Hospital were retrospectively analysed. The Cox regression model was used to analyse the correlation between the PFR and other clinicopathological factors in overall survival (OS) and disease-free survival (DFS). Results Cox regression analysis showed that the PFR (hazard ratio (HR)=2.123; 95% confidence interval (95% CI), 1.271-3.547; P=0.004) was an independent risk factor affecting the OS of HCC patients. Furthermore, a nomogram was built based on these risk factors. The C-index for the OS nomogram was 0.715. Conclusions Nomograms based on the PFR can be recommended as the correct and actual model to evaluate the prognosis of patients with HCC.
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Affiliation(s)
- Haixi Yan
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Shuaishuai Chen
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Department of Clinical Laboratory, Linhai, Zhejiang Province, China
| | - Yang Qiong
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Department of Clinical Laboratory, Linhai, Zhejiang Province, China
| | - Linling Cai
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Department of Clinical Laboratory, Linhai, Zhejiang Province, China
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22
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Wilder CS, Chen Z, DiGiovanni J. Pharmacologic approaches to amino acid depletion for cancer therapy. Mol Carcinog 2021; 61:127-152. [PMID: 34534385 DOI: 10.1002/mc.23349] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/27/2021] [Accepted: 09/02/2021] [Indexed: 11/09/2022]
Abstract
Cancer cells undergo metabolic reprogramming to support increased demands in bioenergetics and biosynthesis and to maintain reactive oxygen species at optimum levels. As metabolic alterations are broadly observed across many cancer types, metabolic reprogramming is considered a hallmark of cancer. A metabolic alteration commonly seen in cancer cells is an increased demand for certain amino acids. Amino acids are involved in a wide range of cellular functions, including proliferation, redox balance, bioenergetic and biosynthesis support, and homeostatic functions. Thus, targeting amino acid dependency in cancer is an attractive strategy for a number of cancers. In particular, pharmacologically mediated amino acid depletion has been evaluated as a cancer treatment option for several cancers. Amino acids that have been investigated for the feasibility of drug-induced depletion in preclinical and clinical studies for cancer treatment include arginine, asparagine, cysteine, glutamine, lysine, and methionine. In this review, we will summarize the status of current research on pharmacologically mediated amino acid depletion as a strategy for cancer treatment and potential chemotherapeutic combinations that synergize with amino acid depletion to further inhibit tumor growth and progression.
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Affiliation(s)
- Carly S Wilder
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
| | - Zhao Chen
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
| | - John DiGiovanni
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA.,Center for Molecular Carcinogenesis and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
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23
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Hatta MNA, Mohamad Hanif EA, Chin SF, Neoh HM. Pathogens and Carcinogenesis: A Review. BIOLOGY 2021; 10:533. [PMID: 34203649 PMCID: PMC8232153 DOI: 10.3390/biology10060533] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/30/2021] [Accepted: 06/02/2021] [Indexed: 12/24/2022]
Abstract
Cancer is a global health problem associated with genetics and unhealthy lifestyles. Increasingly, pathogenic infections have also been identified as contributors to human cancer initiation and progression. Most pathogens (bacteria, viruses, fungi, and parasites) associated with human cancers are categorized as Group I human carcinogens by the International Agency for Research on Cancer, IARC. These pathogens cause carcinogenesis via three known mechanisms: persistent infection that cause inflammation and DNA damage, initiation of oncogene expression, and immunosuppression activity of the host. In this review, we discuss the carcinogenesis mechanism of ten pathogens, their implications, and some future considerations for better management of the disease. The pathogens and cancers described are Helicobacter pylori (gastric cancer), Epstein-Barr virus (gastric cancer and lymphoma), Hepatitis B and C viruses (liver cancer), Aspergillus spp. (liver cancer), Opisthorchis viverrine (bile duct cancer), Clonorchis sinensis (bile duct cancer), Fusobacterium nucleatum (colorectal cancer), Schistosoma haematobium (bladder cancer); Human Papillomavirus (cervical cancer), and Kaposi's Sarcoma Herpes Virus (Kaposi's sarcoma).
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Affiliation(s)
| | | | | | - Hui-min Neoh
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Ya’acob Latiff, Cheras, Kuala Lumpur 56000, Malaysia; (M.N.A.H.); (E.A.M.H.); (S.-F.C.)
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24
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Bian R, Dang W, Song X, Liu L, Jiang C, Yang Y, Li Y, Li L, Li X, Hu Y, Bao R, Liu Y. Rac GTPase activating protein 1 promotes gallbladder cancer via binding DNA ligase 3 to reduce apoptosis. Int J Biol Sci 2021; 17:2167-2180. [PMID: 34239347 PMCID: PMC8241731 DOI: 10.7150/ijbs.58857] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/30/2021] [Indexed: 11/09/2022] Open
Abstract
Rac GTPase activating protein 1 (RACGAP1) has been characterized in the pathogenesis and progression of several malignancies, however, little is known regarding its role in the development of gallbladder cancer (GBC). This investigation seeks to describe the role of RACGAP1 and its associated molecular mechanisms in GBC. It was found that RACGAP1 was highly expressed in human GBC tissues, which was associated to poorer overall survival (OS). Gene knockdown of RACGAP1 hindered tumor cell proliferation and survival both in vitro and in vivo. We further identified that RACGAP1 was involved in DNA repair through its binding with DNA ligase 3 (LIG3), a crucial component of the alternative-non-homologous end joining (Alt-NHEJ) pathway. RACGAP1 regulated LIG3 expression independent of RhoA activity. RACGAP1 knockdown resulted in LIG3-dependent repair dysfunction, accumulated DNA damage and Poly(ADP-ribosyl) modification (PARylation) enhancement, leading to increased apoptosis and suppressed cell growth. We conclude that RACGAP1 exerts a tumor-promoting role via binding LIG3 to reduce apoptosis and facilitate cell growth in GBC, pointing to RACGAP1 as a potential therapeutic target for GBC.
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Affiliation(s)
- Rui Bian
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Wei Dang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Xiaoling Song
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Liguo Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Chengkai Jiang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yang Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yongsheng Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Lin Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Xuechuan Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yunping Hu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Runfa Bao
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
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Aune D, Sen A, Norat T, Riboli E, Folseraas T. Primary sclerosing cholangitis and the risk of cancer, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of cohort studies. Sci Rep 2021; 11:10646. [PMID: 34017024 PMCID: PMC8137938 DOI: 10.1038/s41598-021-90175-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 05/07/2021] [Indexed: 02/03/2023] Open
Abstract
A diagnosis of primary sclerosing cholangitis (PSC) has been associated with increased risk of hepatobiliary cancers, colorectal cancer and all-cause mortality in several studies, while associations with cardiovascular disease have been inconsistent. We conducted a systematic review and meta-analysis of published cohort studies on the topic to summarize these associations. PubMed and Embase databases were searched up to January 13th, 2020. Cohort studies on PSC and risk of cancer, cardiovascular disease, or mortality were included. Summary relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated using random effects models. The summary RR (95% CI) comparing persons with PSC to persons without PSC was 584.37 (269.42-1267.51, I2 = 89%, n = 4) for cholangiocarcinoma (CCA), 155.54 (125.34-193.02, I2 = 0%, n = 3) for hepatobiliary cancer, 30.22 (11.99-76.17, I2 = 0%, n = 2) for liver cancer, 16.92 (8.73-32.78, I2 = 88%, n = 4) for gastrointestinal cancer, 7.56 (2.42-23.62, I2 = 0%, n = 3) for pancreatic cancer, 6.10 (4.19-8.87, I2 = 14%, n = 7) for colorectal cancer (CRC), 4.13 (2.99-5.71, I2 = 80%, n = 5) for total cancer, 3.55 (2.94-4.28, I2 = 46%, n = 5) for all-cause mortality, and 1.57 (0.25-9.69, I2 = 79%, n = 2) for cardiovascular disease. Strong positive associations were observed between PSC and risk of CCA, hepatobiliary cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, CRC, total cancer, and all-cause mortality, but not for cardiovascular disease.
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Affiliation(s)
- Dagfinn Aune
- grid.7445.20000 0001 2113 8111Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St. Mary’s Campus, Norfolk Place, Paddington, London, W2 1PG UK ,grid.510411.00000 0004 0578 6882Department of Nutrition, Bjørknes University College, Oslo, Norway ,grid.55325.340000 0004 0389 8485Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital Ullevål, Oslo, Norway ,grid.4714.60000 0004 1937 0626Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Abhijit Sen
- grid.5947.f0000 0001 1516 2393Department of Public Health and Nursing, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway ,Center for Oral Health Services and Research (TkMidt), Trondheim, Norway
| | - Teresa Norat
- grid.7445.20000 0001 2113 8111Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St. Mary’s Campus, Norfolk Place, Paddington, London, W2 1PG UK
| | - Elio Riboli
- grid.7445.20000 0001 2113 8111Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St. Mary’s Campus, Norfolk Place, Paddington, London, W2 1PG UK
| | - Trine Folseraas
- grid.55325.340000 0004 0389 8485Division of Surgery, Inflammatory Medicine and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway ,grid.5510.10000 0004 1936 8921Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway ,grid.55325.340000 0004 0389 8485Division of Surgery, Inflammatory Medicine and Transplantation, Section for Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
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26
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Wang Y, Zhu L, Xu D, Gao L, Li Y, Liang B, Zhang X, Yue Y. Intrahepatic Cholestasis of Pregnancy Is Associated with Reduced Nitric Oxide Synthase (iNOS) in Plasma and Placentas: A Pilot Study. Med Sci Monit 2021; 27:e930176. [PMID: 33846282 PMCID: PMC8052913 DOI: 10.12659/msm.930176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background Intrahepatic cholestasis of pregnancy (ICP) is a condition specific to pregnancy, leading to increased fetal morbidity and mortality. Nitric oxide synthase (iNOS) may be a factor regulating the vasodilation of blood vessels, which are relevant to ischemic-hypoxic conditions. We aimed to explore the potential relationship between iNOS and ICP. Material/Methods A prospective, case-control study was conducted including 77 pregnant women with ICP and 80 healthy pregnant women as controls. Enzyme-linked immunosorbent assays were used to investigate maternal plasma iNOS levels. The placenta mRNA levels and cell-specific localization of iNOS were determined by quantitative polymerase chain reaction, western blotting, and immunohistochemical analysis. A multivariate linear regression model was used to identify the independent factors of serum total biliary acids (TAB) in ICP. Results Compared with controls, the expression of iNOS was significantly lower in maternal serum and placentas with ICP (P<0.001). Maternal plasm iNOS levels were negatively correlated with TAB (r=−0.450, P<0.001), cholyglycine (r=−0.367, P<0.001), alanine aminotransferase (r=−.359, P<0.001), and aspartate aminotransferase (r=−0.329, P<0.001). iNOS level was an indicator for ICP by multivariate linear regression analysis (β=−0.505, P<0.001). The ROC curve indicated the optimal cut-off level for iNOS was 2865.43 pg/mL (sensitivity, 85.71%; specificity, 63.75%). The ROC curve area for iNOS was 0.793 (95% CI 0.722–0.864). Conclusions iNOS plays an important role in poor fetoplacental vascular perfusion and adverse pregnancy outcomes. iNOS can provide complementary information in predicting the extent and severity of ICP.
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Affiliation(s)
- Yun Wang
- Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China (mainland)
| | - Liping Zhu
- Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China (mainland)
| | - Duo Xu
- Department of Obstetrics and Gynecology, Shenzhen Maternity and Child Healthcare Hospital Affiliated with Southern Medical University, Shenzhen, Guangdong, China (mainland)
| | - Liying Gao
- Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China (mainland)
| | - Yongmei Li
- Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China (mainland)
| | - Baoquan Liang
- Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China (mainland)
| | - Xiaoqian Zhang
- Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China (mainland)
| | - Yongfei Yue
- Department of Obstetrics and Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China (mainland)
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27
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Leone V, Ali A, Weber A, Tschaharganeh DF, Heikenwalder M. Liver Inflammation and Hepatobiliary Cancers. Trends Cancer 2021; 7:606-623. [PMID: 33674229 DOI: 10.1016/j.trecan.2021.01.012] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 12/17/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023]
Abstract
Immune regulation has an important role in cancer development, particularly in organs with continuous exposure to environmental pathogens, such as the liver and gastrointestinal tract. Chronic liver inflammation can lead to the development of hepatobiliary cancers, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or combined HCC (cHCC)-CCA. In this review, we discuss the link between oxidative stress and the hepatic immune compartments, as well as how these factors trigger hepatocyte damage, proliferation, and eventually cancer initiation and its sustainment. We further give an overview of new anticancer therapies based on immunomodulation.
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Affiliation(s)
- Valentina Leone
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Research Unit Radiation Cytogenetics, Helmholtz Zentrum München Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany
| | - Adnan Ali
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Achim Weber
- Department of Pathology and Molecular Pathology, Institute of Molecular Cancer Research (IMCR), University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland
| | - Darjus Felix Tschaharganeh
- Helmholtz-University Group Cell Plasticity and Epigenetic Remodeling, German Cancer Research Center (DKFZ) and Institute of Pathology University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
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28
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Mintz J, Vedenko A, Rosete O, Shah K, Goldstein G, Hare JM, Ramasamy R, Arora H. Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics. Vaccines (Basel) 2021; 9:94. [PMID: 33513777 PMCID: PMC7912608 DOI: 10.3390/vaccines9020094] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide (NO) is a short-lived, ubiquitous signaling molecule that affects numerous critical functions in the body. There are markedly conflicting findings in the literature regarding the bimodal effects of NO in carcinogenesis and tumor progression, which has important consequences for treatment. Several preclinical and clinical studies have suggested that both pro- and antitumorigenic effects of NO depend on multiple aspects, including, but not limited to, tissue of generation, the level of production, the oxidative/reductive (redox) environment in which this radical is generated, the presence or absence of NO transduction elements, and the tumor microenvironment. Generally, there are four major categories of NO-based anticancer therapies: NO donors, phosphodiesterase inhibitors (PDE-i), soluble guanylyl cyclase (sGC) activators, and immunomodulators. Of these, NO donors are well studied, well characterized, and also the most promising. In this study, we review the current knowledge in this area, with an emphasis placed on the role of NO as an anticancer therapy and dysregulated molecular interactions during the evolution of cancer, highlighting the strategies that may aid in the targeting of cancer.
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Affiliation(s)
- Joel Mintz
- Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Davie, FL 33328, USA;
| | - Anastasia Vedenko
- John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (A.V.); (J.M.H.)
| | - Omar Rosete
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Khushi Shah
- College of Arts and Sciences, University of Miami, Miami, FL 33146, USA;
| | - Gabriella Goldstein
- College of Health Professions and Sciences, University of Central Florida, Orlando, FL 32816, USA;
| | - Joshua M. Hare
- John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (A.V.); (J.M.H.)
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Medicine, Cardiology Division, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Ranjith Ramasamy
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Himanshu Arora
- John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (A.V.); (J.M.H.)
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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Corrao S, Natoli G, Argano C. Nonalcoholic fatty liver disease is associated with intrahepatic cholangiocarcinoma and not with extrahepatic form: definitive evidence from meta-analysis and trial sequential analysis. Eur J Gastroenterol Hepatol 2021; 33:62-68. [PMID: 32091438 DOI: 10.1097/meg.0000000000001684] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cholangiocarcinoma is a cancer with poor prognosis. The detection of risk factors is fundamental to identify subjects at higher risk of cholangiocarcinoma. Nonalcoholic fatty liver disease (NAFLD) represents a leading cause of chronic liver disease worldwide. Recent data suggested that NAFLD increases the risk of cholangiocarcinoma development. However, it is necessary to better explain the strength of association between NAFLD and cholangiocarcinoma. METHODS A systematic research of current case-control, cohort, clinical trial and meta-analysis on the main electronic databases was made. A recent systematic review was recognized. We performed cumulative meta-analyses with sensitivity analysis excluding studies with large sample size and with great clinical heterogeneity, then we checked for further studies. At the final step, three trial sequential analyses were done as well. RESULTS NAFLD determines an increased risk of total cholangiocarcinoma and intrahepatic cholangiocarcinoma (iCCA) development: odds ratio (OR) (95% confidence interval [CI]): 1.88 (1.25-2.83), OR (95% CI): 2.19 (1.48-3.25), respectively. On the contrary, NAFLD does not show a significant effect on extrahepatic cholangiocarcinoma (eCCA) (OR (95% CI): 1.48 (0.93-2.36). The trial sequential analyses regarding total cholangiocarcinoma and iCCA showed that z-curve was outside computed alpha boundaries, proving that the positive association was conclusive. The trial sequential analysis about eCCA showed that z-curve was inside computed futile boundaries, proving that negative results were conclusive. CONCLUSION The performance of new sensitive analyses and the respective trial sequential analyses, after withdraw of confounding factors, suggested the existence of definitive association only between NAFLD and iCCA development and not with eCCA.
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Affiliation(s)
- Salvatore Corrao
- 2nd Internal Medicine Department, National Relevance Hospital Trust, ARNAS Civico, Di Cristina e Benfratelli
- Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro", (PROMISE) University of Palermo, Palermo, Italy
| | - Giuseppe Natoli
- 2nd Internal Medicine Department, National Relevance Hospital Trust, ARNAS Civico, Di Cristina e Benfratelli
| | - Christiano Argano
- 2nd Internal Medicine Department, National Relevance Hospital Trust, ARNAS Civico, Di Cristina e Benfratelli
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30
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Khan FH, Dervan E, Bhattacharyya DD, McAuliffe JD, Miranda KM, Glynn SA. The Role of Nitric Oxide in Cancer: Master Regulator or NOt? Int J Mol Sci 2020; 21:ijms21249393. [PMID: 33321789 PMCID: PMC7763974 DOI: 10.3390/ijms21249393] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Nitric oxide (NO) is a key player in both the development and suppression of tumourigenesis depending on the source and concentration of NO. In this review, we discuss the mechanisms by which NO induces DNA damage, influences the DNA damage repair response, and subsequently modulates cell cycle arrest. In some circumstances, NO induces cell cycle arrest and apoptosis protecting against tumourigenesis. NO in other scenarios can cause a delay in cell cycle progression, allowing for aberrant DNA repair that promotes the accumulation of mutations and tumour heterogeneity. Within the tumour microenvironment, low to moderate levels of NO derived from tumour and endothelial cells can activate angiogenesis and epithelial-to-mesenchymal transition, promoting an aggressive phenotype. In contrast, high levels of NO derived from inducible nitric oxide synthase (iNOS) expressing M1 and Th1 polarised macrophages and lymphocytes may exert an anti-tumour effect protecting against cancer. It is important to note that the existing evidence on immunomodulation is mainly based on murine iNOS studies which produce higher fluxes of NO than human iNOS. Finally, we discuss different strategies to target NO related pathways therapeutically. Collectively, we present a picture of NO as a master regulator of cancer development and progression.
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Affiliation(s)
- Faizan H. Khan
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Eoin Dervan
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Dibyangana D. Bhattacharyya
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Jake D. McAuliffe
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Katrina M. Miranda
- Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA;
| | - Sharon A. Glynn
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
- Correspondence:
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31
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Sirica AE, Strazzabosco M, Cadamuro M. Intrahepatic cholangiocarcinoma: Morpho-molecular pathology, tumor reactive microenvironment, and malignant progression. Adv Cancer Res 2020; 149:321-387. [PMID: 33579427 PMCID: PMC8800451 DOI: 10.1016/bs.acr.2020.10.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a relatively rare, but highly lethal and biologically complex primary biliary epithelial cancer arising within liver. After hepatocellular carcinoma, iCCA is the second most common primary liver cancer, accounting for approximately 10-20% of all primary hepatic malignancies. Over the last 10-20 years, iCCA has become the focus of increasing concern largely due to its rising incidence and high mortality rates in various parts of the world, including the United States. The challenges posed by iCCA are daunting and despite recent progress in the standard of care and management options for iCCA, the prognosis for this cancer continues to be dismal. In an effort to provide a framework for advancing our understanding of iCCA malignant aggressiveness and therapy resistance, this review will highlight key etiological, biological, molecular, and microenvironmental factors hindering more effective management of this hepatobiliary cancer. Particular focus will be on critically reviewing the cell origins and morpho-molecular heterogeneity of iCCAs, providing mechanistic insights into high risk fibroinflammatory cholangiopathies associated with iCCA development, and notably discussing the deleterious role played by the tumor reactive desmoplastic stroma in regulating iCCA malignant progression, lymphangiogenesis, and tumor immunobiology.
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Affiliation(s)
- Alphonse E Sirica
- Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA, United States.
| | - Mario Strazzabosco
- Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States
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Yang Q, Ouyang J, Sun F, Yang J. Short-Chain Fatty Acids: A Soldier Fighting Against Inflammation and Protecting From Tumorigenesis in People With Diabetes. Front Immunol 2020; 11:590685. [PMID: 33363537 PMCID: PMC7752775 DOI: 10.3389/fimmu.2020.590685] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/03/2020] [Indexed: 12/16/2022] Open
Abstract
Converging evidences showed that people with diabetes mellitus (DM) have significantly higher risk for different cancers, of which the exact mechanism underlying the association has not been fully realized. Short-chain fatty acids (SCFAs), the fermentation products of the intestinal microbiota, are an essential source for energy supply in gut epithelial cells. They have been reported to improve intestinal barrier integrity, prevent microbial translocation, and further dampen inflammation. Gut dysbiosis and reduction in SCFA-producing bacteria as well as SCFAs production in the intestine are commonly seen in metabolic disorders including DM and obesity. Moreover, inflammation can contribute to tumor initiation and progression through multiple pathways, such as enhancing DNA damage, accumulating mutations in tumor suppressor genes Tp53, and activating nuclear factor-kappa B (NF-κB) signaling pathways. Based on these facts, we hypothesize that lower levels of microbial SCFAs resulted from gut dysbiosis in diabetic individuals, enhance microbial translocation, and increase the inflammatory responses, inducing tumorigenesis ulteriorly. To this end, we will discuss protective properties of microbial SCFAs and explore the pivotal roles SCFAs played in the link of DM with cancer, so as to take early precautions to reduce the risk of cancer in patients with DM.
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Affiliation(s)
- Qiyu Yang
- Department of Radiation Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Hospital, Chongqing, China
| | - Jing Ouyang
- Chongqing Public Health Medical Center, Chongqing, China
| | - Fengjun Sun
- Department of Pharmacy, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China
| | - Jiadan Yang
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Nitric oxide-inducing Genistein elicits apoptosis-like death via an intense SOS response in Escherichia coli. Appl Microbiol Biotechnol 2020; 104:10711-10724. [PMID: 33170329 DOI: 10.1007/s00253-020-11003-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 10/26/2020] [Accepted: 11/03/2020] [Indexed: 01/06/2023]
Abstract
Increasing prevalence of multidrug-resistant untreatable infections has prompted researchers to trial alternative treatments such as a substitute for traditional antibiotics. This study endeavored to elucidate the antibacterial mechanism(s) of this isoflavone, via analysis of relationship between genistein and Escherichia coli. Furthermore, this investigation analyzed whether genistein generates nitric oxide (NO) in E. coli as NO contributes to cell death. RecA, an essential protein for the bacterial SOS response, was detected through western blot, and the activated caspases decreased without RecA. The results showed that the NO induced by genistein affected the bacterial DNA. Under conditions of acute DNA damage, an SOS response called apoptosis-like death occurred, affecting DNA repair. These results suggested that RecA was bacterial caspase-like protein. In addition, NO was toxic to the bacterial cells and induced dysfunction of the plasma membrane. Thus, membrane depolarization and phosphatidylserine exposure were observed similarly to eukaryotic apoptosis. In conclusion, the combined results demonstrated that the antibacterial mode of action(s) of genistein was a NO-induced apoptosis-like death, and the role of RecA suggested that it contributed to the SOS response of NO defense. KEY POINTS: • Genistein generates nitric oxide in E. coli. • Genistein exhibits intense SOS response in E. coli. • Genistein-induced NO causes apoptosis-like death in E. coli.
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Protection from Ultraviolet Damage and Photocarcinogenesis by Vitamin D Compounds. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1268:227-253. [PMID: 32918222 DOI: 10.1007/978-3-030-46227-7_12] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, may cause mutations. UV-induced DNA damage and reactive oxygen and nitrogen species also cause local and systemic suppression of the adaptive immune system. Together, these changes underpin the development of skin tumours. The hormone derived from vitamin D, calcitriol (1,25-dihydroxyvitamin D3) and other related compounds, working via the vitamin D receptor and at least in part through endoplasmic reticulum protein 57 (ERp57), reduce cyclobutane pyrimidine dimers and oxidative DNA damage in keratinocytes and other skin cell types after UV. Calcitriol and related compounds enhance DNA repair in keratinocytes, in part through decreased reactive oxygen species, increased p53 expression and/or activation, increased repair proteins and increased energy availability in the cell when calcitriol is present after UV exposure. There is mitochondrial damage in keratinocytes after UV. In the presence of calcitriol, but not vehicle, glycolysis is increased after UV, along with increased energy-conserving autophagy and changes consistent with enhanced mitophagy. Reduced DNA damage and reduced ROS/RNS should help reduce UV-induced immune suppression. Reduced UV immune suppression is observed after topical treatment with calcitriol and related compounds in hairless mice. These protective effects of calcitriol and related compounds presumably contribute to the observed reduction in skin tumour formation in mice after chronic exposure to UV followed by topical post-irradiation treatment with calcitriol and some, though not all, related compounds.
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Singh S. Updates on Versatile Role of Putative Gasotransmitter Nitric Oxide: Culprit in Neurodegenerative Disease Pathology. ACS Chem Neurosci 2020; 11:2407-2415. [PMID: 32564594 DOI: 10.1021/acschemneuro.0c00230] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Nitric oxide (NO) is a versatile gasotransmitter that contributes in a range of physiological and pathological mechanims depending on its cellular levels. An appropriate concentration of NO is essentially required for cellular physiology; however, its increased level triggers pathological mechanisms like altered cellular redox regulation, functional impairment of mitochondrion, and modifications in cellular proteins and DNA. Its increased levels also exhibit post-translational modifications in protein through S-nitrosylation of their thiol amino acids, which critically affect the cellular physiology. Along with such modifications, NO could also nitrosylate the endoplasmic reticulum (ER)-membrane located sensors of ER stress, which subsequently affect the cellular protein degradation capacity and lead to aggregation of misfolded/unfolded proteins. Since protein aggregation is one of the pathological hallmarks of neurodegenerative disease, NO should be taken into account during development of disease therapies. In this Review, we shed light on the diverse role of NO in both cellular physiology and pathology and discussed its involvement in various pathological events in the context of neurodegenerative diseases.
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Affiliation(s)
- Sarika Singh
- Department of Neurosciences and Ageing Biology and Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India
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Wan ZH, Jiang TY, Shi YY, Pan YF, Lin YK, Ma YH, Yang C, Feng XF, Huang LF, Kong XN, Ding ZW, Tan YX, Dong LW, Wang HY. RPB5-Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding. Hepatology 2020; 71:2005-2022. [PMID: 31541481 DOI: 10.1002/hep.30962] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 09/16/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5-mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression. APPROACH AND RESULTS RMP-overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch-like ECH-associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP-KEAP1-NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis. CONCLUSION These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies.
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Affiliation(s)
- Zheng-Hua Wan
- National Center for Liver Cancer, the Second Military Medical University, Shanghai, China.,No. 971 Hospital of Peoples' Liberation Army Navy, Qing Dao, China
| | - Tian-Yi Jiang
- National Center for Liver Cancer, the Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, China
| | - Yuan-Yuan Shi
- National Center for Liver Cancer, the Second Military Medical University, Shanghai, China
| | - Yu-Fei Pan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, China
| | - Yun-Kai Lin
- National Center for Liver Cancer, the Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, China
| | - Yun-Han Ma
- National Center for Liver Cancer, the Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, China
| | - Chun Yang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, China.,Children's Hospital of Soochow University, Suzhou, China
| | - Xiao-Fan Feng
- National Center for Liver Cancer, the Second Military Medical University, Shanghai, China
| | - Li-Feng Huang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Ni Kong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Wen Ding
- National Center for Liver Cancer, the Second Military Medical University, Shanghai, China
| | - Ye-Xiong Tan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, China
| | - Li-Wei Dong
- National Center for Liver Cancer, the Second Military Medical University, Shanghai, China
| | - Hong-Yang Wang
- National Center for Liver Cancer, the Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, The Second Military Medical University & Ministry of Education, Shanghai, China
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37
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The therapeutic potential of second and third generation CB1R antagonists. Pharmacol Ther 2020; 208:107477. [DOI: 10.1016/j.pharmthera.2020.107477] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 01/02/2020] [Indexed: 12/25/2022]
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Abstract
Exposure to arsenic in contaminated drinking water is an emerging public health problem that impacts more than 200 million people worldwide. Accumulating lines of evidence from epidemiological studies revealed that chronic exposure to arsenic can result in various human diseases including cancer, type 2 diabetes, and neurodegenerative disorders. Arsenic is also classified as a Group I human carcinogen. In this review, we survey extensively different modes of action for arsenic-induced carcinogenesis, with focus being placed on arsenic-mediated impairment of DNA repair pathways. Inorganic arsenic can be bioactivated by methylation, and the ensuing products are highly genotoxic. Bioactivation of arsenicals also elicits the production of reactive oxygen and nitrogen species (ROS and RNS), which can directly damage DNA and modify cysteine residues in proteins. Results from recent studies suggest zinc finger proteins as crucial molecular targets for direct binding to As3+ or for modifications by arsenic-induced ROS/RNS, which may constitute a common mechanism underlying arsenic-induced perturbations of DNA repair.
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Chen Z, Zhou Q, Liu C, Zeng Y, Yuan S. Klotho deficiency aggravates diabetes-induced podocyte injury due to DNA damage caused by mitochondrial dysfunction. Int J Med Sci 2020; 17:2763-2772. [PMID: 33162804 PMCID: PMC7645346 DOI: 10.7150/ijms.49690] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/09/2020] [Indexed: 01/20/2023] Open
Abstract
Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury inducing glomerular filtration barrier and proteinuria. The occurrence and development of DN could be partly attributed to the reactive oxygen species (ROS) generated by mitochondria. However, research on how mitochondrial dysfunction (MtD) ultimately causes DNA damage is poor. Here, we investigated the influence of Klotho deficiency on high glucose (HG)-induced DNA damage in vivo and in vitro. First, we found that the absence of Klotho aggravated diabetic phenotypes indicated by podocyte injury accompanied by elevated urea albumin creatinine ratio (UACR), creatinine and urea nitrogen. Then, we further confirmed that Klotho deficiency could significantly aggravate DNA damage by increasing 8-OHdG and reducing OGG1. Finally, we demonstrated Klotho deficiency may promote MtD to promote 8-OHdG-induced podocyte injury. Therefore, we came to a conclusion that Klotho deficiency may promote diabetes-induced podocytic MtD and aggravate 8-OHdG-induced DNA damage by affecting OOG1.
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Affiliation(s)
- Zhi Chen
- University-Town Clinic, 958 hospital of PLA Army, Chongqing, 400020, People's Republic of China
| | - Qing Zhou
- School of Military Preventive Medicine, Army Military Medical University, Chongqing, 400020, People's Republic of China
| | - Cong Liu
- Center of Laboratory Medicine, Chongqing Prevention and Treatment Center for Occupational Disease, Chongqing, 400060, People's Republic of China
| | - Yiping Zeng
- Department of orthopedics, Chongqing general hospital, University of Chinese Academy of Sciences, Chongqing, 400014, People's Republic of China
| | - Shaolong Yuan
- University-Town Clinic, 958 hospital of PLA Army, Chongqing, 400020, People's Republic of China
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40
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Radiation-Induced Normal Tissue Damage: Oxidative Stress and Epigenetic Mechanisms. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3010342. [PMID: 31781332 PMCID: PMC6875293 DOI: 10.1155/2019/3010342] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 10/23/2019] [Accepted: 10/24/2019] [Indexed: 01/23/2023]
Abstract
Radiotherapy (RT) is currently one of the leading treatments for various cancers; however, it may cause damage to healthy tissue, with both short-term and long-term side effects. Severe radiation-induced normal tissue damage (RINTD) frequently has a significant influence on the progress of RT and the survival and prognosis of patients. The redox system has been shown to play an important role in the early and late effects of RINTD. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the main sources of RINTD. The free radicals produced by irradiation can upregulate several enzymes including nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), lipoxygenases (LOXs), nitric oxide synthase (NOS), and cyclooxygenases (COXs). These enzymes are expressed in distinct ways in various cells, tissues, and organs and participate in the RINTD process through different regulatory mechanisms. In recent years, several studies have demonstrated that epigenetic modulators play an important role in the RINTD process. Epigenetic modifications primarily contain noncoding RNA regulation, histone modifications, and DNA methylation. In this article, we will review the role of oxidative stress and epigenetic mechanisms in radiation damage, and explore possible prophylactic and therapeutic strategies for RINTD.
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Gurmikov BN, Kovalenko YA, Vishnevsky VA, Chzhao AV. Molecular genetic aspects of intrahepatic cholangiocarcinoma: literature review. ADVANCES IN MOLECULAR ONCOLOGY 2019. [DOI: 10.17650/2313-805x-2019-6-1-37-43] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- B. N. Gurmikov
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
| | - Yu. A. Kovalenko
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
| | - V. A. Vishnevsky
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
| | - A. V. Chzhao
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
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Mortezaee K, Najafi M, Farhood B, Ahmadi A, Shabeeb D, Musa AE. NF‐κB targeting for overcoming tumor resistance and normal tissues toxicity. J Cell Physiol 2019; 234:17187-17204. [DOI: 10.1002/jcp.28504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 02/22/2019] [Accepted: 03/05/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Keywan Mortezaee
- Department of Anatomy School of Medicine, Kurdistan University of Medical Sciences Sanandaj Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department School of Paramedical Sciences, Kermanshah University of Medical Sciences Kermanshah Iran
| | - Bagher Farhood
- Departments of Medical Physics and Radiology Faculty of Paramedical Sciences, Kashan University of Medical Sciences Kashan Iran
| | - Amirhossein Ahmadi
- Pharmaceutical Sciences Research Center Faculty of Pharmacy, Mazandaran University of Medical Sciences Sari Iran
| | - Dheyauldeen Shabeeb
- Department of Physiology College of Medicine, University of Misan Misan Iraq
| | - Ahmed E. Musa
- Department of Medical Physics Tehran University of Medical Sciences (International Campus) Tehran Iran
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Labib PL, Goodchild G, Pereira SP. Molecular Pathogenesis of Cholangiocarcinoma. BMC Cancer 2019; 19:185. [PMID: 30819129 PMCID: PMC6394015 DOI: 10.1186/s12885-019-5391-0] [Citation(s) in RCA: 200] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 02/20/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis. CONCLUSION Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.
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Affiliation(s)
- Peter L. Labib
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - George Goodchild
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - Stephen P. Pereira
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
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Alnajjar KS, Sweasy JB. A new perspective on oxidation of DNA repair proteins and cancer. DNA Repair (Amst) 2019; 76:60-69. [PMID: 30818170 DOI: 10.1016/j.dnarep.2019.02.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 02/07/2019] [Indexed: 02/07/2023]
Abstract
Reactive oxygen and nitrogen species (RONS) are formed as byproducts of many endogenous cellular processes, in response to infections, and upon exposure to various environmental factors. An increase in RONS can saturate the antioxidation system and leads to oxidative stress. Consequently, macromolecules are targeted for oxidative modifications, including DNA and protein. The oxidation of DNA, which leads to base modification and formation of abasic sites along with single and double strand breaks, has been extensively investigated. Protein oxidation is often neglected and is only recently being recognized as an important regulatory mechanism of various DNA repair proteins. This is a review of the current state of research on the regulation of DNA repair by protein oxidation with emphasis on the correlation between inflammation and cancer.
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Affiliation(s)
- Khadijeh S Alnajjar
- Department of Therapeutic Radiology and Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, United States.
| | - Joann B Sweasy
- Department of Therapeutic Radiology and Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, United States
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Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies. Int J Mol Sci 2018; 19:ijms19123875. [PMID: 30518128 PMCID: PMC6321547 DOI: 10.3390/ijms19123875] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 11/29/2018] [Accepted: 12/01/2018] [Indexed: 02/08/2023] Open
Abstract
The cholangipathies are a class of liver diseases that specifically affects the biliary tree. These pathologies may have different etiologies (genetic, autoimmune, viral, or toxic) but all of them are characterized by a stark inflammatory infiltrate, increasing overtime, accompanied by an excess of periportal fibrosis. The cellular types that mount the regenerative/reparative hepatic response to the damage belong to different lineages, including cholagiocytes, mesenchymal and inflammatory cells, which dynamically interact with each other, exchanging different signals acting in autocrine and paracrine fashion. Those messengers may be proinflammatory cytokines and profibrotic chemokines (IL-1, and 6; CXCL1, 10 and 12, or MCP-1), morphogens (Notch, Hedgehog, and WNT/β-catenin signal pathways) and finally growth factors (VEGF, PDGF, and TGFβ, among others). In this review we will focus on the main molecular mechanisms mediating the establishment of a fibroinflammatory liver response that, if perpetuated, can lead not only to organ dysfunction but also to neoplastic transformation. Primary Sclerosing Cholangitis and Congenital Hepatic Fibrosis/Caroli’s disease, two chronic cholangiopathies, known to be prodrome of cholangiocarcinoma, for which several murine models are also available, were also used to further dissect the mechanisms of fibroinflammation leading to tumor development.
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Najafi M, Motevaseli E, Shirazi A, Geraily G, Rezaeyan A, Norouzi F, Rezapoor S, Abdollahi H. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: clinical implications. Int J Radiat Biol 2018; 94:335-356. [PMID: 29504497 DOI: 10.1080/09553002.2018.1440092] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 01/23/2018] [Accepted: 01/31/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE Cancer treatment is one of the most challenging diseases in the present era. Among a few modalities for cancer therapy, radiotherapy plays a pivotal role in more than half of all treatments alone or combined with other cancer treatment modalities. Management of normal tissue toxicity induced by radiation is one of the most important limiting factors for an appropriate radiation treatment course. The evaluation of mechanisms of normal tissue toxicity has shown that immune responses especially inflammatory responses play a key role in both early and late side effects of exposure to ionizing radiation (IR). DNA damage and cell death, as well as damage to some organelles such as mitochondria initiate several signaling pathways that result in the response of immune cells. Massive cell damage which is a common phenomenon following exposure to a high dose of IR cause secretion of a lot of inflammatory mediators including cytokines and chemokines. These mediators initiate different changes in normal tissues that may continue for a long time after irradiation. In this study, we reviewed the mechanisms of inflammatory responses to IR that are involved in normal tissue toxicity and considered as the most important limiting factors in radiotherapy. Also, we introduced some agents that have been proposed for management of these responses. CONCLUSIONS The early inflammation during the radiation treatment is often a limiting factor in radiotherapy. In addition to the limiting factors, chronic inflammatory responses may increase the risk of second primary cancers through continuous free radical production, attenuation of tumor suppressor genes, and activation of oncogenes. Moreover, these effects may influence non-irradiated tissues through a mechanism named bystander effect.
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Affiliation(s)
- Masoud Najafi
- a Radiology and Nuclear Medicine Department, School of Paramedical Sciences , Kermanshah University of Medical Science , Kermanshah , Iran
| | - Elahe Motevaseli
- b Department of Molecular Medicine, School of Advanced Technologies in Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Alireza Shirazi
- c Department of Medical Physics and Biomedical Engineering, Faculty of Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Ghazale Geraily
- c Department of Medical Physics and Biomedical Engineering, Faculty of Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Abolhasan Rezaeyan
- d Department of Medical Physics, School of Medicine , Iran University of Medical Sciences , Tehran , Iran
| | - Farzad Norouzi
- e Science and Research Branch , Azad University , Tehran , Iran
| | - Saeed Rezapoor
- f Department of Radiology, Faculty of Paramedical Sciences , Tehran University of Medical Sciences , Tehran , Iran
| | - Hamid Abdollahi
- d Department of Medical Physics, School of Medicine , Iran University of Medical Sciences , Tehran , Iran
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Nitric Oxide and Mitochondrial Function in Neurological Diseases. Neuroscience 2018; 376:48-71. [DOI: 10.1016/j.neuroscience.2018.02.017] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 01/20/2018] [Accepted: 02/09/2018] [Indexed: 12/17/2022]
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48
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Wongjarupong N, Assavapongpaiboon B, Susantitaphong P, Cheungpasitporn W, Treeprasertsuk S, Rerknimitr R, Chaiteerakij R. Non-alcoholic fatty liver disease as a risk factor for cholangiocarcinoma: a systematic review and meta-analysis. BMC Gastroenterol 2017; 17:149. [PMID: 29216833 PMCID: PMC5721586 DOI: 10.1186/s12876-017-0696-4] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2017] [Accepted: 11/20/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has been recently identified as a risk factor of gastrointestinal tract cancers, especially hepatocellular carcinoma, and colorectal cancer. Whether NAFLD is a risk factor for cholangiocarcinoma (CCA) remains inconclusive. The aim of this study is to determine a potential association between NAFLD and CCA, stratifying by its subtypes; intrahepatic CCA (iCCA), and extrahepatic CCA (eCCA). METHODS A search was conducted for relevant studies published up to April 2017 using MEDLINE, EMBASE, Scopus and Cochrane databases. Odds ratio (OR) and adjusted OR with 95% confidence interval (CI) were estimated using a random-effects model. Subgroup analyses were conducted with study characteristics. RESULTS Seven case-control studies were included in the analysis, with a total of 9,102 CCA patients (5,067 iCCA and 4,035 eCCA) and 129,111 controls. Overall, NAFLD was associated with an increased risk for CCA, with pooled OR of 1.95 (95%CI: 1.36-2.79, I 2 =76%). When classified by subtypes, NAFLD was associated with both iCCA and eCCA, with ORs of 2.22 (95%CI: 1.52-3.24, I 2 =67%) and 1.55 (95%CI: 1.03-2.33, I 2 =69%), respectively. The overall pooled adjusted ORs were 1.97 (95%CI: 1.41-2.75, I 2 =71%), 2.09 (95%CI, 1.49-2.91, I 2 =42%) and 2.05 (95%CI, 1.59-2.64, I 2 =0%) for all CCAs, iCCA, and eCCA, respectively. CONCLUSIONS This meta-analysis suggests that NAFLD may potentially increase the risk of CCA development. The magnitude of NAFLD on CCA risk is greater for iCCA than eCCA subtype, suggestive of a common pathogenesis of iCCA and hepatocellular carcinoma. Further studies to confirm this association are warranted. TRIAL REGISTRATION The protocol for this study was registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42016046573).
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Affiliation(s)
- Nicha Wongjarupong
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, 1873 Rama IV Road, Patumwan, Bangkok, 10330 Thailand
- Department of Physiology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Buravej Assavapongpaiboon
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, 1873 Rama IV Road, Patumwan, Bangkok, 10330 Thailand
- Department of Parasitology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Paweena Susantitaphong
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | | | - Sombat Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, 1873 Rama IV Road, Patumwan, Bangkok, 10330 Thailand
| | - Rungsun Rerknimitr
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, 1873 Rama IV Road, Patumwan, Bangkok, 10330 Thailand
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, 1873 Rama IV Road, Patumwan, Bangkok, 10330 Thailand
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Wei MY, Tang ZH, Quan ZW. Intrahepatic cholangiocarcinoma: Role of metabolism in pathogenesis, clinical diagnosis, and treatment. Shijie Huaren Xiaohua Zazhi 2017; 25:2929-2937. [DOI: 10.11569/wcjd.v25.i33.2929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Recent studies demonstrated that metabolism plays an important role in the pathogenesis, clinical diagnosis, and treatment of intrahepatic cholangiocarcinoma (ICC). The mechanisms of several metabolic enzymes associated with ICC, including pyruvate kinase M2 (PKM2), thymidine synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), isocitric acid dehydrogenase 1/2 (IDH1/2), and cyclo-oxygenase-2 (COX-2), have been gradually clarified and hopefully transformed into clinical application in the future. Besides, ICC patients always have concomitant abnormal lipid metabolism, which has attracted the attention of clinicians and researchers. Metabolites in serum and bile have potential diagnostic utility, which has yet to be verified by prospective clinical research. 18F-FDG PET/CT based on metabolism presents application value in many aspects of ICC, such as diagnosis, staging, evaluation of therapeutic effect, and monitoring prognosis. In this article, we review the recent progress in the understanding of the role of metabolism in ICC from both basic and clinical perspectives, with an aim to highlight the further research directions and accelerate the clinical transformation.
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Affiliation(s)
- Miao-Yan Wei
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Zhao-Hui Tang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Zhi-Wei Quan
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
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Bragazzi MC, Ridola L, Safarikia S, Matteo SD, Costantini D, Nevi L, Cardinale V. New insights into cholangiocarcinoma: multiple stems and related cell lineages of origin. Ann Gastroenterol 2017; 31:42-55. [PMID: 29333066 PMCID: PMC5759612 DOI: 10.20524/aog.2017.0209] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 09/14/2017] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that may develop at any level of the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) on the basis of its anatomical location. Notably, although these three CCA subtypes have common features, they also have important inter- and intra-tumor differences that can affect their pathogenesis and outcome. A unique feature of CCA is that it manifests in the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, furnished by two distinct stem cell niches: the canals of Hering and the peribiliary glands, respectively. The complexity of CCA pathogenesis highlights the need for a multidisciplinary, translational, and systemic approach to this malignancy. This review focuses on advances in the knowledge of CCA histomorphology, risk factors, molecular pathogenesis, and subsets of CCA.
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Affiliation(s)
- Maria Consiglia Bragazzi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Ridola
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Samira Safarikia
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Sabina Di Matteo
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Daniele Costantini
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Nevi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
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